Inflammatory reaction is accompanied by infiltration of leukocytes, typically neutrophils and lymphocytes, into inflammatory sites.
Infiltration of leukocytes is defined as migration of leukocytes such as neutrophils and lymphocytes out of vessels and into the surrounding tissues as a consequence of initiation and activation by cytokines, chemokines, lipids and complement to interact called “rolling” or “tethering” with vascular endothelial cells activated by cytokines such as IL-1 or TNFα, followed by adhesion to the vascular endothelial cells.
As explained below, relationship between leukocyte adhesion or infiltration and various inflammatory diseases and autoimmune diseases was reported. Such reports have raised the possibility that compounds having cell adhesion inhibitory action or cell infiltration inhibitory action may serve as therapeutic or prophylactic agents for such diseases.    (1) Therapeutic or prophylactic agents for inflammatory bowel disease (ulcerative colitis, Crohn's disease and the like) (see Non-patent documents 1, 2 and 3)    (2) Therapeutic or prophylactic agents for irritable bowel syndrome (see Non-patent document 4)    (3) Therapeutic or prophylactic agents for rheumatoid arthritis (see Non-patent document 5)    (4) Therapeutic or prophylactic agents for psoriasis (see Non-patent document 6)    (5) Therapeutic or prophylactic agents for multiple sclerosis (see Non-patent document 7)    (6) Therapeutic or prophylactic agents for asthma (see Non-patent document 8)    (7) Therapeutic or prophylactic agents for atopic dermatitis (see Non-patent document 9)
Thus, substances which inhibit cell adhesion or cell infiltration are expected to be useful as therapeutic or prophylactic agents for inflammatory diseases and autoimmune diseases and as therapeutic or prophylactic agents for various diseases associated with adhesion and infiltration of leukocytes, such as inflammatory bowel disease (particularly ulcerative colitis or Crohn's disease), irritable bowel syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, asthma and atopic dermatitis.
Compounds are also known which have anti-inflammatory action based on inhibition of adhesion of leukocyte and vascular endothelial cell, or anti-inflammatory action based on inhibition of leukocyte infiltration (these will hereinafter be referred to as cell adhesion inhibitors and cell infiltration inhibitors, respectively), such as the following compound:
(see Patent document 1).
However, the compounds represented by general formula (1) according to the present invention are characterized by including a partial chemical structure having piperazine or piperidine at the ortho position of a benzene ring bonded to an aliphatic carbocyclic group such as cyclohexyl, therefore differ in their structures from the aforementioned cell adhesion inhibitors or cell infiltration inhibitors.
The known compound comprising a partial chemical structure having piperazine or piperidine at the ortho position of a benzene ring bonded to an aliphatic carbocyclic group such as cyclohexyl, as a chemical structural feature of the compounds represented by general formula (1) according to the present invention, is the compound represented by the following formula:
(see Patent document 2).
However, the patent application discloses only its use as an anti-obesity agent and diabetes treatment based on the melanocortin receptor agonistic activity of the compound, while it neither discloses nor suggests its use as an anti-inflammatory agent based on inhibitory action of leukocyte adhesion or infiltration.
Other than the above compound, the compound represented by the following formula:
is known (see Non-patent document 10, compound number 45).    [Patent document 1] WO 2002/018320    [Patent document 2] WO 2002/059108    [Non-patent document 1] Inflammatory Bowel Disease (N. Engl. J. Med., 347:417-429 (2002))    [Non-patent document 2] Natalizumab for active Crohn's disease (N. Engl. J. Med., 348:24-32 (2003))    [Non-patent document 3] Granulocyte adsorption therapy in active period of ulcerative colitis (Japanese Journal of Apheresis 18:117-131 (1999))    [Non-patent document 4] A role for inflammation in irritable bowel syndrome (Gut., 51: i41-i44 (2002))    [Non-patent document 5] Rheumatoid arthritis (Int. J. Biochem. Cell Biol., 36:372-378 (2004))    [Non-patent document 6] Psoriasis (Lancet, 361:1197-1204 (2003))    [Non-patent document 7] New and emerging treatment options for multiple sclerosis (Lancet Neurology, 2:563-566 (2003))    [Non-patent document 8] The role of T lymphocytes in the pathogenesis of asthma (J. Allergy Clin. Immunol., 111:450-463 (2003)    [Non-patent document 9] The molecular basis of lymphocyte recruitment to the skin (J. Invest. Dermatol., 121:951-962 (2003))    [Non-patent document 10] Discovery of 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a dopaminergic agent with a novel mode of action for the potential treatment of erectile dysfunction (J. Med. Chem., 47: 3853-3864 (2004))